The overall goal of this research program is to understand the mechanism of signal transduction mediated by MAP kinases in mammalian cells. A focus of this study is the c-Jun NH2-terminal kinase (JNK) group of MAP kinases. Many of the components of the JNK protein kinase cascade have been identified by molecular cloning and have been characterized in biochemical studies. However, a complete understanding of the physiological function of JNK has remained elusive. The long-term goal of this research is to define the molecular mechanisms and physiological significance of JNK activation in neurons. A specific focus of our analysis will be to determine the role of JNK in neurodegeneration. Achievement of the goals of this proposal will increase understanding of the molecular mechanism of MAP kinase signal transduction in vivo. This information represents a basis for the design of novel therapeutic strategies for the treatment of neurodegenerative diseases, including stroke. The Specific Aims of this proposal are to examine: 1. The physiological role of JNK in neurons. 2. The mechanism of JNK-induced neurodegeneration.